DESCRIPTION(Adapted from applicant's abstract): The kainate subtypes of glutamate receptor are the last to have been cloned and the least well understood, largely due to a lack of pharmacologic tools. We recently found that several forms of modulation previously thought to mBuence only NMDA receptors (protons, spermine, Zn2+, ifenprodil, dynorphin, redox conditions) also control kainate receptor activation in a subunit-selective manner. The physiological roles of kainate receptors are ill-defined but are likely to include control of interneuron network function in the hippocampus. The following specific aims have the goal of determining the synaptic roles played by kainate receptors in the hippocampal interneuron network, and the secondary objective of elucidating the structural basis for modulation at these newly-discovered allosteric sites. 1) to characterize the subunit-dependence and mechanisms for inhibition of kainate receptors by protons and zinc. 2) to test the hypothesis that zinc released from mossy fiber terminals depresses kainate receptor-mediated EPSCs in a pH and frequency-sensitive manner. 3) to identify noncompetitive, subunit-specific and pH-sensitive antagonists of heteromeric kainate and GluR2lacking AMPA receptors. 4) to test the hypothesis that activation of kainate receptors on presynaptic axonal terminals reduces transmitter release, and to determine whether postsynaptic kainate receptors on hippocarnpal pyraimidal cells and different internouron populations contribute to synaptic plasticity or integration. A combination of molecular biological and electrophysiological approaches will be used in these studies. The successful cornpletion of these experiments will substantially in prove our understanding of the synaptic roles of kainate receptors in the hippocampus, will elucidate the subunit-dependence and mechanisms of action of several newly-discovered kainate receptor modulators, will shed light on the physiological function of synaptically-released zinc, and will identify the first noncompetitive antagonists selective for kainate receptors.